Undetermined leukodystrophies constitute a group of diseases for which the responsible gene has not yet been identified or is in the process of being identified. Together, these account for 30% of leukodystrophies.

Undetermined leukodystrophies are extremely rare diseases that are difficult to identify and diagnose.

These include:

  • Pigmented orthochromatic leukodystrophy
  • Leukodystrophy with progressive ataxia, deafness and cardiomyopathy
  • Leukodystrophy with oligodontia and hypomyelination

In the majority of cases, the disease is so rare that it is difficult to even give it a name.

Magnetic resonance imaging (MRI) makes it possible to explore the brain and shows up any white matter anomalies. The diagnosis of undetermined leukodystrophy is only made when possible diagnosis of other similar disease has been eliminated.

It is important not to confuse undetermined leukodystrophies with other diseases such as:

- white-matter anomalies of non-genetic origin ; which may have circulatory , infectious, toxic or inflammatory causes,

- white-matter signal modifications observed in many genetic diseases, especially metabolic disorders, but without primitive myelin deficiency.

While the clinical context, the MRI and certain specific tests will generally enable us to eliminate these causes, it is important to be aware that doubts may remain. Indeed, leukodystrophies caused by hereditary problems concerning the myelin formation of the central nervous system often appear, in childhood, as non-progressive illness, although sometimes cerebral lesions acquired during the prenatal, or perinatal period can appear to be evolve because of changes in how they manifest as the brain matures.

It is also important not to confuse them with the identified leukodystrophies. Some leukodystrophies have biological markers that make it possible to identify them by a blood or urine test, or even a cerebrospinal fluid test. These possibilities must be systematically explored before arriving at a diagnosis of undetrmined leukodystrophy, even though their manifestations vary hugely, especially according to the patient's age.

Other leukodystrophies can be recognized by a set of indicators gleaned from the clinical presentation, the mode of genetic transmission and the results of medical examinations, particularly radiological (scanner and MRI) and electrophysiological examinations. A biopsy of nerve tissue may also prove revelatory.

Rigorous assessment, careful observation of the evolution of the disease and the repetition of key medical examinations must all be accomplished before a diagnosis of leukodystrophy of unknown etiology can be made.

The vast heterogeneity of undetermined leukodystrophies makes them particularly difficult to study.

To make progress, we need to:

  • identify homogenous subgroups of patients so as to be able to apply molecular genetic methods. Research needs to be undertaken on a European or even international scale and the establishment of a network organization would help speed up the identification of homogenous subgroups of patients and optimize molecular research that can lead to identification of the responsible gene;
  • use new investigative techniques: magnetic resonance spectroscopy can help us find new biological markers; new techniques for cellular analysis (immunofluorescence, in situ hybridization) will help inform gene therapy and genetic counseling;
  • identify the causal genes, and with this in view, we need to conserve and immortalize all blood samples, taken from patients and their families, in liquid nitrogen, so as to have a store of quantities of DNA for when that becomes useful.

In conclusion, the role played by the families of patients affected by undetermined leukodystrophy is of utmost importance: the more information is shared, and the more families group together and make contact with the research laboratories, the better we will understand these very rare diseases.